This invention relates to the fields of organic synthesis, asymmetric synthesis, catalysis, combinatorial catalysis, organoboron chemistry, combinatorial chemistry and medicinal chemistry. More specifically, the invention relates to methods for preparing chiral amine or amino alcohols used to prepare chiral reagents or catalysts which can be used for the synthesis of many other molecules.
Although many chiral reagents or catalysts containing chiral amine or amino alcohol ligands and their methods of synthesis are known, these often have limited effectiveness giving products with high enantiomeric excess (%ee) only in certain cases. Most synthetic routes to chiral amines or amino alcohols proceed with low or mixed stereoselectivity, involve multiple steps, allow only limited types of substituents, or require highly reactive organometallics that involve cumbersome experimental conditions and necessitate additional protection-deprotection steps.
Rather than rely on the identification of a globally effective catalyst system, the present invention allows the facile construction of stereochemically pure amine or amino alcohol ligands that are subsequently used to form chiral reagents or catalysts. These can be prepared either individually or as combinatorial libraries and can be used to easily identify the most suitable catalyst for a given transformation.
A key feature of the present invention is the construction of amine or amino alcohol ligands in one or two steps and in high enantiomeric and diastereomeric purity.
This invention relates to a practical and effective method for the stereocontrolled synthesis of amines or amino alcohols for the preparation of a large variety of chiral catalysts for asymmetric synthesis. This process involves the one-step combination of certain organoboron derivatives, including organoboronic acids, organoboronates and organoborates with primary or secondary amines and certain carbonyl derivatives, such as xcex1-keto acids, xcex1-hydroxy aldehydes or carbohydrates. This process constitutes a three-component reaction and is suitable for the rapid generation of combinatorial libraries of amine or amino alcohols. These products can be converted to chiral reagents or catalysts via a subsequent reaction with an appropriate reagent, which can be present as a fourth component or can be used in a follow-up step.
The synthetic procedure is quite simple and works in a variety of solvents, including water, ethanol, dichloromethane and toluene. Product isolation is often very simple and can give fairly pure products without the need for chromatography or distillation. Of special significance is the fact that this process generates new Cxe2x80x94C bonds with very high stereoselectivity (up to more than 99% de and 99% ee) when certain chiral components are used in the reaction. Due to its operational simplicity and the fact that no hazardous chemicals or special precautions are required, this invention is suitable for the practical and convenient synthesis of many types of amine or amino alcohol ligands, including stereochemically pure derivatives. These molecules can then serve as components of chiral reagents or catalysts which are useful for the synthesis of a variety of chiral organic molecules. In this manner, this invention is useful for the preparation of various chemicals, pharmaceuticals and agrochemicals.
Definitions:
An organoboron derivative, as defined herein, comprises a compound having a boron atom connected to at least one alkyl, allyl, alkenyl, aryl, allenyl or alkynyl group.
Alkyl groups of the present invention include straight-chained, branched and cyclic alkyl radicals containing up to about 20 carbons. Suitable alkyl groups may be saturated or unsaturated. Further, an alkyl may also be substituted one or more times on one or more carbons with substituents selected from the group consisting of C1-C6 alkyl, C3-C6 heterocycle, aryl, halo, hydroxy, amino, alkoxy and sulfonyl. Additionally, an alkyl group may contain up to 10 heteroatoms or heteroatom substituents. Suitable heteroatoms include nitrogen, oxygen, sulfur and phosphorous.
Aryl groups of the present invention include aryl radicals which may contain up to 10 heteroatoms. An aryl group may also be optionally substituted one or more times with an aryl group or a lower alkyl group and it may be also fused to other aryl or cycloalkyl rings. Suitable aryl groups include, for example, phenyl, naphthyl, tolyl, imidazolyl, pyridyl, pyrroyl, thienyl, pyrimidyl, thiazolyl and furyl groups.
The term xe2x80x9ccombinatorial libraryxe2x80x9d as used herein refers to a set of compounds that are made by the same process, by varying one or more of the reagents. Combinatorial libraries may be made as mixtures of compounds, or as individual pure compounds, generally depending on the methods used for identifying active compounds. Where the active compound may be easily identified and distinguished from other compounds present by physical and/or chemical characteristics, it may be preferred to provide the library as a large mixture of compounds. Large combinatorial libraries may also be prepared by massively parallel synthesis of individual compounds, in which case compounds are typically identified by their position within an array. Intermediate between these two strategies is xe2x80x9cdeconvolutionxe2x80x9d, in which the library is prepared as a set of sub-pools, each having a known element and a random element. For example, using the process of the invention each sub-pool might be prepared from only a single amine (where each sub-pool contains a different amine), but a mixture of different carbonyl derivatives (or organoboron reagents). When a sub-pool is identified as having desired activity, it is resynthesized as a set of individual compounds (each compound having been present in the original active sub-pool), and tested again to identify the compounds responsible for the activity of the sub-pool.
The term xe2x80x9cMetalxe2x80x9d means any metal, metal derivative, or metal substitute useful for performing the a reaction in order to synthesize a reagant or catalyst. Examples include, but are not limited to B, Li, Mg, Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Mo, Ru, Rh, Pd, Ag, Re, Os, Ir, Pt, La, Ce and Yb.
General Description:
The first step of this invention involves a novel synthesis of a chiral amine or amino alcohol ligand and the second step involves the conversion of this amine or amino alcohol to a chiral reagent or catalyst.
The first step is based on the use of organoboron compounds in a Cxe2x80x94C bond forming reaction where the electrophile is derived from a carbonyl and an amine and the product is a new substituted amine. There are many variations of this methodology involving different organoboron, carbonyl and amine components. For the purpose of illustration the following variations are described here.
Synthesis of Chiral Amines:
One aspect of the invention is a process for generating chiral amine derivatives of formula (1) or a combinatorial library of molecules of formula (1), by combining compounds (2), (3) and (4): 
where R1 and R2 are each independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, acyl, carboxy, carboxamido, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, and xe2x80x94YR, where Y is selected from the group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NRaxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, and xe2x80x94SO2xe2x80x94, and R and Ra are each independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, and acyl, or R1 and R2 together form a methylene bridge of 2 to 20 carbon atoms; and where R3 and R4 are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl; aryl, and heteroaryl; and where R5 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl; R6, R7 are selected from the group consisting of hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, and heteroaryl, or together form a methylene bridge of 3 to 7 atoms.
Following their formation, compounds of formula (1) can be subsequently easily transformed to new derivatives. For example, removing groups R1 and R2 can provide primary amines, while joining two or more groups will result in the formation of cyclic or polycyclic amines.
The multicomponent nature of the process described in this invention allows the direct and rapid generation of combinatorial libraries of individual products or mixtures of products, by varying the desired substituents. Such libraries can be generated either in solution or in the solid phase, upon attachment of one substituent onto a solid support. For example, one may couple the amine component (2) to a substrate through either R1 or R2, and react the immobilized amine to a mixture of different organoboron compounds (3), where R5 is a variety of different groups) and individual or mixed carbonyl compounds (4) to produce a mixture of bound products (1). Alternatively, the carbonyl compound may be immobilized, and a mixture of organoboron compounds and diverse amines added. Combinatorial libraries may be generated either as individual compounds or as mixtures of compounds.
In another embodiment of the invention an organoboron compound of formula (8) is combined with a preformed iminium derivative (5), aminol (6), or aminal (7), prepared by the combination of an amine (2) and a carbonyl compound (3), or by other methods: 
where R5 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl; R6, R7 and R8 are selected from the group consisting of hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, and heteroaryl, or together form a methylene bridge of 3 to 7 atoms; X is a positive counter ion, and n is 0 or 1. Such reactions can take place directly or upon the addition of a Lewis acid. In the case of fluoroborates (8) R6=R7=R8=F) the, reaction may be promoted by the addition of a silyl derivative SiR9R10R11R12, where R9 is selected from the groups consisting of: chloro, bromo, iodo, alkoxy acyloxy, triflate, alkylsulfonate or arylsulfonate, while substituents R10, R11 and R12 are selected from the groups consisting of: alkyl, cycloalkyl, aryl, alkoxy, aryloxy or chloro. A preferred R5 is an alkenyl or aryl group leading to the formation of geometrically and isomerically pure allylamines or benzylamines (2), respectively.
Synthesis of Chiral xcex1-Amino Carbonyl Derivatives:
This invention can be employed directly for the synthesis of chiral xcex1-amino acids or other xcex1-amino carbonyl derivatives (10) by combining an organoboron compound (4) with an amine (2) and an xcex1-dicarbonyl compound (9). 
The reaction can proceed directly in a variety of solvents, including water, alcohols, ethers, hydrocarbons, chlorinated hydrocarbons and acetonitrile.
The stereochemistry of the product in these reactions can be controlled by the use of a chiral amine, a chiral carbonyl compound or a chiral organoboron derivative (L. Deloux et al., Chem. Rev. (1993) 93:763). The use of chiral amines or similar amino alcohol or amino acid derivatives can give products with a high degree of diastereocontrol (up to 99.5%de). Removal of the chiral group substituent can give the free amino acid with a high enantiomeric excess (up to 99.5%ee).
The types of organoboron compounds that can be used in this manner include compounds (4) that have R5 selected from the group consisting of alkyl, allyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl, including substituted and isomerically pure derivatives. The boron substituents R6 and R7 which do not appear in the product (10), are selected from the groups consisting of: hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, heteroaryl, including substituted and isomerically pure derivatives. Groups R6 and R7 may be connected together to form a bridge of 3 to 7 atoms. Substituents R3 in compound (9) are selected from the group consisting of hydrogen, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, hydroxyamino, alkyl, cycloalkyl, aryl, hetero aryl, including substituted and isomerically pure derivatives. Substituents R4 in compound (9) are selected from the group consisting of hydrogen, carboxy, alkyl, cycloalkyl, aryl, hetero aryl, including substituted and isomerically pure derivatives. Substituents R1 and R2 in amine (2) are selected from the groups consisting of: alkyl, cycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, alkylthio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl or arylsulfonyl, including substituted and isomerically pure derivatives. Groups R1 and R2 may be connected together to form a bridge of 2 to 20 atoms.
The reactants are combined in approximately equimolar amounts in the solvent, and maintained at a temperature between about 0xc2x0 C. and the reflux temperature of the solvent, preferably between about 25xc2x0 C. and about 65xc2x0 C., until the reaction is complete. The course of the reaction may be followed by any standard method, including thin-layer chromatography, GC and HPLC. In general, the reaction is conducted for about 1 to about 72 hours, preferably about 12 to about 24 hours. Product isolation usually gives fairly pure products without the need for chromatography or distillation.
The products (10) of the invention can be subsequently transformed to produce new derivatives. For example, if R3 is hydroxyl, removing groups R1 and R2 can provide primary amino acids, while joining two or more groups will result in the formation of cyclic or polycyclic derivatives. A number of amine components (2) can be used which include R1 and R2 groups that can be easily removed in subsequent reactions. For example, benzylamine derivatives can be cleaved by hydrogenation, while others, such as the di(p-anisyl)methylamino group or the trityl group, can be removed under acidic conditions which prevent facile racemization.
The multicomponent nature of the process described in this invention allows the direct and rapid generation of combinatorial libraries of the products, by varying the desired substituents. Such libraries can be generated either in solution or in the solid phase, upon attachment of one substituent onto a solid support. In this case at least one of the groups R1 through R7 is a polymeric material. For example, one may couple an amine (2) to a substrate through either R1 or R2, and react the immobilized amine with a mixture of different organoboron compounds (4) (where R5 is a variety of different groups) and individual or mixed dicarbonyl compounds (9) to produce bound products (10). Alternatively, the dicarbonyl compound may be immobilized, and a mixture of organoboron compounds and diverse amines added. Combinatorial libraries may be generated either as individual compounds or as mixtures of compounds.
In order to improve the potential use of compounds (10) in the synthesis of chiral reagents or catalysts, additional steps may be carried out. For example, if compound (10) is an amino acid or amino ester (R3xe2x95x90OH or OR) it can be converted to an amino alcohol of formula (11) by reduction. Alternatively, if R3 in compound (10) is an amino group, reduction will lead to a diamine of formula (12). 
Synthesis of Chiral N-carboxymethyl Amino Acid Derivatives:
The use of xcex1-amino acid derivatives (13) as the amine components in this process, can lead to N-carboxymethyl amino acid products (14) with a very high degree of diastereocontrol. 
Substituents R1 and R2 in the amino acid component (13) are selected from the group consisting of alkyl, cycloalkyl, aryl, hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl and arylsulfonyl, including substituted and isomerically pure derivatives. Groups R1 and R2 may also be connected to other amino acid units (peptides) or may be connected together to form a bridge of 2 to 20 atoms. Groups R8 and R9 are selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, acyl and carboxy,including substituted and isomerically pure derivatives. Groups R8 and R9 may be connected together or with other groups in (13), (9), or (4) to form a bridge of 3 to 7 atoms. Substituents R3 and R4 in compound (9) are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, aryloxy, heteroaryloxy, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, and heteroaryl. The boron substitutent R5 in (4) is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl. The boron substituents R6 and R7 which do not appear in the products, are selected from the group consisting of hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl and heteroaryl, including substituted and isomerically pure derivatives.
In order to improve the potential use of compounds (14) in the synthesis of chiral reagents or catalysts, additional steps may be carried out. For example, different variations of compound (14) can be converted to an amino diol of formula (15), a diamine alcohol of formula (16) or a triamine of formula (17). 
Synthesis of Chiral 1,2-Diamines and 1,2-Amino Alcohols:
In another embodiment of the invention an amine (2) and an organoboron compound are reacted with carbonyl derivatives of the general formula (18) to give products (19). 
Groups R1 and R2 in the amine component (2) are selected from the groups consisting of: alkyl, cycloalkyl, aryl, hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl or arylsulfonyl, including substituted and isomerically pure derivatives. Groups R1 and R2 may be connected together to form a bridge of 2 to 20 atoms. Groups R3 in compound (18) are selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl. Groups R3 in compound (18) have at, least one carbon atom and are attached to a group XH, where X is selected from a group consisting of xe2x80x94Oxe2x80x94, xe2x80x94NRaxe2x80x94, xe2x80x94Sxe2x80x94, and Ra is independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, acyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino, dialkylamino, and acylamino. The boron substitutent R5 in compound (4) is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl. The boron substituents R6 and R7 which do not appear in the products, are selected from the groups consisting of: hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, heteroaryl, including substituted and isomerically pure derivatives. Groups R6 and R7 may be connected together to form a bridge of 3 to 7 atoms.
In one embodiment of the invention an amine (2) and an organoboron compound (4) are reacted with xcex1-amino carbonyl derivatives (20) to give directly 1,2-diamines (21). 
Groups R1 and R2 in the amine component (2) are selected from the groups consisting of: alkyl, cycloalkyl, aryl, hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl or arylsulfonyl, including substituted and isomerically pure derivatives. Groups R1 and R2 may be connected together to form a bridge of 2 to 20 atoms. Groups R3, R4 and R8 in compound (20) are selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl. Groups R9 and R10 in compound (20) are selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl and arylsulfonyl, including substituted and isomerically pure derivatives. Groups R9 and R10 may be connected with other groups in compounds (2), (20) or (4) to form a bridge of 2 to 20 atoms. The boron substitutent R5 in compound (4) is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl. The boron substituents R6 and R7 which do not appear in the products, are selected from the group consisting of hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl and heteroaryl, including substituted and isomerically pure derivatives. Groups R6 and R7 may be connected together to form a bridge of 3 to 7 atoms.
The products (21) of the invention can be subsequently transformed to produce new derivatives. For example, removing groups R1 and R2 can provide primary amines, while joining two or more groups will result in the formation of cyclic or polycyclic derivatives. A number of amine components (2) can be used which include R1 and R2 groups that can be easily removed in subsequent reactions. For example, benzylamine derivatives can be cleaved by hydrogenation, while others, such as the di(p-anisyl)methylamino group or the trityl group, can be removed under acidic conditions which prevent facile racemization.
In another embodiment of the invention an amine (2) and an organoboron compound are reacted with an xcex1-hydroxy carbonyl derivative (22) to give 1,2-amino alcohols (23). Compounds (22) can also exist in a hemiacetal form, and can include carbohydrate derivatives. The use of chiral derivatives (22) can form products (23) with a very high degree of diastereocontrol (up to greater than 99.5%de) and enantiocontrol diastereocontrol (up to greater than 99.5%ee). 
Groups R1 and R2 in the amine component (2) are selected from the group consisting of alkyl, cycloalkyl, aryl, hetero aryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, alkyl thio, arylthio, acylthio, trialkylsilyl, aryldialkylsilyl, diarylalkylsilyl, triarylsilyl, phosphinyl, alkylsulfonyl and arylsulfonyl, including substituted and isomerically pure derivatives. Groups R1 and R2 may be connected with other groups in compounds (2), (22) or (4) to form a bridge of 2 to 20 atoms. Groups R3, R4 and R8 in compound (22) are selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, and heteroaryl. The boron substitutent R5 in compound (4) is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, alkenyl, alkynyl and allenyl. The boron substituents R6 and R7 which do not appear in the products, are selected from the groups consisting of: hydroxy, alkoxy, aryloxy, heteroaryloxy, chloro, bromo, fluoro, iodo, carboxy, amino, alkylamino, dialkylamino, acylamino, carboxamido, thio, alkylthio, arylthio, acylthio, alkyl, cycloalkyl, aryl, heteroaryl, including substituted and isomerically pure derivatives. Groups R6 and R7 may be connected together to form a bridge of 3 to 7 atoms.
An important feature of this variation is that when optically pure alpha-hydroxy carbonyl compounds (22) are used, no racemization occurs and the products (23) can be obtained as single enantiomers, with greater than 99% ee.
The products (23) of the invention can be subsequently transformed to produce new derivatives. For example, removing groups R1 and R2 can provide primary amines, while joining two or more groups will result in the formation of cyclic or polycyclic derivatives. A number of amine components (2) can be used which include R1 and R2 groups that can be easily removed in subsequent reactions. For example, benzylamine derivatives can be cleaved by hydrogenation, while others, such as the di(p-anisyl)methylamino group or the trityl group, can be removed under acidic conditions which prevent facile racemization. Also, the use of groups R5 in the organoboron component, such as alkenyl or activated aryl or heteroaryl, followed by oxidative cleavage gives new products where the R5 is a carbonyl group (aldehyde, ketone or carboxylic acid). Alternatively, the use of carbonyl components (22) having a group R4 or R8 consisting of a carbon atom attached to a hydroxyl group, as with many carbohydrate derivatives, followed by oxidative diol cleavage can produce new variations of compounds of the general formula (10).
Synthesis of Chiral Reagents or Catalysts:
The second step of this invention involves the reaction of a ligand derived from the first step, for example a compound of formula (1), (10), (11), (12), (14), (15), (16), (17), (19), (21), or (23) with a compound (24) of the general formula M(L)n to give a new chiral reagent or catalyst that contains one or more bonds among M and a heteroatom of the ligand. 
The atom M in formula (24) is selected from a group consisting of Li, Mg, B, Al, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Mo, Ru, Rh, Pd, Ag, Re, Os, Ir, Pt, La, Ce, Yb; where L is a ligand selected from a group consisting of chloro, bromo, iodo, fluoro, oxo, hydroxy, hydroperoxy, alkoxy, aryloxy, acyloxy, acetoacetyl, carboxy, nitro, amino, alkylamino, dialkylamino, azido, carbonyl, alkyl, alkenyl, dienyl, aryl, triflate, arylsulfonyl; where n is a number selected from 0-6; and where all ligands L are the same or different. Typical reagents of formula (24) include, but are not limited to: ZnBr2, Ti(OR4), Zr(OR)4, YbCl3, CrCl2, WOCl4, FeCl2, RuCl2, CoCl2, NiCl2, PdCl2, CuCl2, ZnCl2, AgOTf, BCl3, AlCl3, etc.
The chiral reagents or catalysts derived during the second step of this invention can be used in a large number of synthetic processes for the preparation of a large variety chiral products. These include: alkylations, aldol reactions, additions of nucleophiles to aldehydes or ketones, additions of nucleophiles to imine derivatives, Diels-Alder reactions, cycloadditions, cyclopropanations, aziridinations, carbonyl reductions, alkene hydrogenations, epoxidations, epoxide opening, etc.
Combinatorial Catalysis:
The facile synthesis of chiral ligands and chiral catalysts with this invention, allows the rapid preparation of large numbers of variants in the form of combinatorial libraries of catalysts. Such libraries can then be used to identify the optimum catalyst for any particular synthetic transformation. Following the screening of the library of catalysts, the most effective one can be easily prepared in large quantities for scale-up.
Solid Phase Variations:
When one of the three components (organoboronic acid, amine, carbonyl) is attached to a solid support, the resulting catalysts will also be attached to the solid support. This variation allows the preparation of even larger libraries via the usual pool and split approach.
Although there are many known methods for the synthesis of amine derivatives, due to the vital importance of these compounds and the many shortcomings of existing methods, any conceptually new and practical method in this are is of special significance. The present method offers a number of advantages over existing methods: Thus, this method is exceptionally environmentally friendly and practical. The reactions can be done in water or aqueous solvents at ambient temperature without using any toxic, hazardous or corrosive materials, such as cyanides, isonitriles, strong acids, strong bases, organotin, organocopper or other highly reactive organometallic compounds. Also, the reaction does not require an inert atmosphere, and can be done in the air. The present method also involves a smaller number of synthetic steps than most existing methods. All starting materials used in this type of reaction are either commercially available or can be readily prepared from commercially available reagents by a one-step procedure.
The use of organoboron compounds, particularly boronic acids and boronates, as nucleophilic components for amino acid and amine synthesis is a new concept which offers a number of distinct features, including the following:
1. Organoboronic acids are often crystalline, easy to prepare and easy to handle compounds that are stable in air and water. They are also non toxic and non hazardous. Although the synthesis and reactivity of these molecules has been studied extensively, the present method is the first successful example of their utilization in the synthesis of amines and amino acids.
2. The present method is highly versatile, allowing a high degree of structural variation in all of the reacting components. The process is also a multi-component reaction, allowing the one-pot construction of amine derivatives from several readily available building blocks. For these reasons, this method is easily applicable to the solid or liquid phase combinatorial synthesis.
3. The stereochemical control of the reaction can be accomplished not only with the use of chiral amine and carbonyl components but also with chiral organoboron derivatives. An advantage of boron-based auxiliaries is that they can be easily introduced and can be efficiently recycled after the reaction, thus making this method especially attractive for large scale applications.
4. Due to the facile synthesis of alkenyl and aryl boron derivatives, which proceed with complete control of geometry or positional isomerism, the present method is uniquely capable of furnishing isomerically pure products of this type.
5. Of special significance is the ability to directly use free amino acids in this reaction to give products of high stereochemical purity.
Although amines and amino alcohols are common ligands for many chiral catalysts, the processes described herein offer numerous advantages including:
1. Most of the existing methods cannot be adapted in a combinatorial approach to catalyst optimization, due to the required multi-step syntheses. While a number of combinatorial approaches to catalyst development were reported, all of these involve more elaborate sequential syntheses or chiral building-block combinations.
2. The present invention, involving a one-step stereocontrolled synthesis of amino alcohols from readily available starting materials, opens the way for the development of a practical combinatorial catalyst synthesis involving these well-established ligands.
3. The fact that the present invention allows the incorporation of multiple hydroxyl groups and other functionalities without any extra protectionxe2x80x94deprotection steps facilitates the synthesis of some really complex chiral catalysts, that may be effective, even though their structures may be difficult to establish.
4. Because aldehyde racemization does not occur under the reaction conditions, relatively enantiomerically pure amino alcohols can be obtained by using enantiomerically pure alpha-hydroxy aldehydes, allowing for greater ease of recovery of the desired product.
5. By having one of the three components (organoboronic acid, amine, carbonyl) attached to a solid support prior to the reaction, the resulting catalysts will also be attached to the support, in a single reaction step. This allows for potentially faster screening of the compounds.
6. The invention allows the preparation of potentially large libraries of chiral catalysts with novel structures that may be used to identify the most effective system for a particular asymmetric transformation.